The action of conventional nonsteroidal antiinflammatories, such as acetylsalicylic acid, is essentially based on the inhibition of cyclooxygenase, an enzyme of the arachidonic acid cascade, which is also known as prostaglandin G/H synthase. Meanwhile, two different forms of cyclooxygenase have been found, which are designated as COX-1 and COX-2. Despite numerous investigations, the biochemical mode of action of the two enzymes is not yet completely elucidated. Various studies have shown, however, that they play an essential role in numerous diseases and inflammatory processes.
Pharmacologically active imidazole compounds which inhibit cyclooxygenase-1 and -2 are already known. In J. Med. Chem. 1996, 39, 3927-37, for example, imidazole derivatives having 5-lipoxygenase- and cyclooxygenase-inhibiting action are described, 2-(4-methylsulfinylphenyl)-4-(4-fluorophenyl-5-(pyrid-4-yl)imidazole also having a cytokine-inhibiting action.
WO 95/00501 describes further phenylheterocycles which have a cyclooxygenase-inhibiting action, among these also 4,5-diaryl-substituted imidazoles, for the treatment of diseases which are connected with cyclooxygenase.
Pharmaceutically active imidazole derivatives are further known which contain 4,5-di-(hetero)arylimidazole elements and are substituted in the 2-position. U.S. Pat. No. 4,585,771 discloses, for example, 4,5-diphenylimidazole derivatives which are substituted in the 2-position by a pyrrolyl, indolyl, imidazolyl or thiazolyl radical and have an antiinflammatory and antiallergic activity. U.S. Pat. Nos. 4,528,298 and 4,402,960 furthermore describe 4,5-di(hetero)arylimidazole derivatives, which are substituted in the 2-position with a phenyl, pyridyl, N-oxypyridyl, pyrimidyl, thiazolyl or thienyl radical, and have an antiinflammatory and antiallergic activity.
DE 198 42 833 relates to 4-heteroaryl-5-phenylimidazole derivatives which are substituted in the 2-position by a phenylalkylthio group. These compounds act as antiinflammatories and inhibitors of cytokine release. WO 99/03837, WO 93/14081 and DE 198 42 833 describe 2-substituted imidazoles which inhibit the synthesis of a number of inflammatory cytokines. These compounds alternatively have a further substituent on the nitrogen atom in the 1-position.
Further pharmacologically active imidazole derivatives are known from U.S. Pat. Nos. 4,461,770, 4,584,310, JP 0140467, DE 28 23 197, EP 372445, WO 91/10662, Acta Chim. 1969, 61, 69-77 and J. Prakt. Chem. 1972, 314, 785-792.
It is known that the conventional nonsteroidal antiinflammatories have a number of undesired side effects, in particular gastrointestinal side effects, nephrotoxicity and allergic reactions. It was further found that the known compounds are not stable and are difficult to process or have a low activity.
In spite of the numerous known compounds, there is therefore furthermore a need for compounds having antiinflammatory, antipyretic and analgesic action, which inhibit the release of various cytokines and serve as inhibitors of the mediators of the arachidonic acid cascade. In particular there is a need for compounds which act not only on the parameters which are decisive in acute diseases, but which also can intervene in the immunological processes crucial for the chronic course (cytokine release, expression of cell-surface antigens). In particular, owing to the importance of the COX enzymes for a number of further pathological processes, e.g.: colon carcinoma, overshooting angiogenesis, excitatory neuronal processes, wound healing etc, the development of COX inhibitors has a novel and additional importance.